N-aryl-n&#39;-aralkyl-diaza cycloalkanes



United States Patent O 3,158,522 N-ARYL-N-AP.ALKYL-DIAZA CYLOALKANES George de Stevens, Woodland Park, Summit, and Robert Paul Mull, Fiorham Parlr, N.J., assignors to Ciha Corporation, New York, N.Y., a corporation of Delaware N Drawing. Filed Oct. 10, 1963, Ser. No. 315,405 29 Claims. (Cl. zen-26s The present invention relates to basic ethers, especially to N-(x-lower alkoxy-x-monocyclic carbocyclic aryl-lower alkyl)-N-monocyclic aryl-diaza-cycloalkanes, in which lower alkoxy and monocyclic carbocyclic aryl substitute the same carbon atom and are separated by two to four carbon atoms from the nitrogen atom of the diaza-cycloalkane portion which has from four to six ring carbon atoms separating the two nitrogen atoms by two to three carbon atoms, and in which monocyclic carbocyclic aryl is phenyl, (lower alky-l)-phenyl, (lower alkoxy)-phenyl, (halogeno)-phenyl or (trifluoromethyD-phenyl, and monocyclic aryl is phenyl, (lower alkyl)-phenyl, (lower alkoxy)-pheny1, (halogeno)-phenyl or pyridyl. More particularly, it relates to compounds having the formula Ph-dnonm. -1 'I IN-Ar 2 in which the group Ph represents phenyl, (lower alkyl) phenyl, (lower alkoxy)-phenyl, (halogeno)phenyl or (trifluoromethyD-phenyl, R stands for lower alkyl, the

group of the formula (C l-lzn) is lower alkylene having from one to six carbon atoms (i.e. the letter 72 stands for an integer from 1 to 6), and separating the carbon atom carrying the groups O-R and Ph from the nitrogen atom by one to three carbon atoms, each of the groups Z and Z stands for alkylene having from two to seven carbon atoms and separating the two nitrogen.

atoms by two to three carbon atoms, and Ar stands for phenyl, (lower alkyl)-phenyl, (lower alkoxy)-phenyl, (halogeno)-phenyl or pyridyl, salts, N-oxides, salts of N-oxides or quaternary ammonium compounds thereof, as well as process for the preparation of these compounds. The monocyclic carbocyclic aryl radical (i.e. the group Phin the above formula), represents phenyl or phenyl substituted by one or more than one of the same or of difierent substituents attached to any of the positions available for substitution in the phenyl nucleus. Substituents are lower alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tertiary butyl and the like, lower alkoxy, e.g. methoxy, ethoxy, n-propyloxy, isopropyloxy, n-butyloxy and the like, halogeno, e.g. fluoro, chloro, bromo and the like, or trifiuoromethyl. The monocyclic carbocyclic aryl group Ph represents primarily phenyl, (lower alky1)-phenyl, (lower alkoxy)-phenyl, (halogeno)-phenyl, or (trifidoromethyD-phenyl.

The lower alkoxy group represented by O-R in the above formula, has from one to seven, preferably from one to four, carbon atoms, and stands above all .for methoxy or ethoxy, as well as for n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, secondary butyloxy, tertiary butyloxy, mpentyloxy, isopentyloxy, n-hexyloxy, n-heptyloxy and the like.

The lower alkylene radical separating lower alkoxy and the monocyclic carbocyclic aryl group Ph from the nitrogen atom of the diaza-cycloalkane porion by two-to four carbon atoms, has from two to seven carbon atoms. Preferably, such radical has from two to four carbon atoms, arranged in an unbranched carbon chain; above alkoxy-Z-monocyclic carbocyclic aryl-ethyl)-N'-monocyclic aryl-diaza-cycloalkane compounds or N-(3-lower 3,168,522 Fairer-tied FelxZ, 1965 alkoxy-3-nionocyclic carbocyclic aryl-propyl)-N-monocyclic aryl-diaza-cycloalkane compounds. In the above formula, the group of the formula (C I-I stands, therefore, for lower alkylene having from one to six carbon atoms (i.e. the letter It stands for an integer from 1 to 6), particularly for methylene (the letter n is l) or 1,2 ethylene (the letter n is 2).

Each of the groups Z and Z in the above formula represents alkylene having from two to seven, preferably from two to three, carbon atoms, and separating the two nitrogen atoms by from two to three carbon atoms. These alkylene radicals are above all 1,2-ethylene or 1,2- propylene, as Well as 1,3-propylene, but may also stand for 1,2-butylene, 2,3-butylene, 1,2-iso-butylene, 1,2-pentylene, 2,3-pentylene, 1,2-isopentylene, 1,2-hexylene, 3,4 hexylene, 3-methyl1,Z-isopentylene, 1,2--heptylene and the like.

The monocyclic aryl group represented by Ar in the above formula, stands primarily for phenyl or phenyl substituted by one or more than one of the same or of diiierent substituents attached to any of the positions available for substitution. Substituents are lower alkyl, eg. methyl, ethyl, n-propyl, isopropyl, tertiary butyl and the like, lower alkoxy, e.g. methoxy, ethoxy, n-pro-pyloxy, isopropyloxy, n-butyloxy and the like, or halogeno, e.g. fiuoro, chloro, bromo and the like. The monocyclic aryl group, such as Ar in the above formula is primarily phenyl, (lower alkyl)-phenyl, (lower alkoxy)-'phenyl, or (halogeno)-phenyl. A monocyclic aryl group, such as Ar in the above formula, also stands for pyridyl, e.g. 2-

Salts of the compounds of this invention are acid addition salts, such as pharmaceutically acceptable, non-toxic addition salts with acids, such as inorganic acids, e.g. hydrochloric, hydrobromic, nitric, sulfuric, phosphoric acids and the like, or organic acids, such as organic carboxylic acids, e.g. acetic, propionic, glycolic, malonic, succinic, maleic, hydroxy-maleic, fumaric, malic, tartaric, citric, benzoic, salicylic, 4-aminosalicylic, Z-acetoxybenzoic, nicotinic, isonicotinic acid and the like, or organic sulfonic acids, eg. methane sulfonic, ethane sulfonic, 2- hydroxy-ethane sulfonic, ethane 1,2-disulfonic, benzene sulfonic, toluene sulfonic, naphthalene 2-sulfonic acid and the like. Other acid addition salts serve as intermediates for the preparation of other acid addition salts, such as pharmaceutically acceptable, non-toxic acid addition salts, or in the purification of the free compounds, as well as for identification and characterization purposes. Acid addition salts primarily used for identification purposes are, for example, those with acidicorganic nitro= compounds, eg. picric, picrolonic, flavianic acid and the like, or with metal complex acids, e.g. phosphotungstic, phosphomolybdic, chloroplatinic, Reinecke acid and the like. Monoor poly-salts may be formed depending on the conditions used for the preparation of the salts.

The compounds of this invention may also be in the Quaternary ammonium derivatives of the compounds of i this invention are those with reactiveesters formetlby alchols and strong acids, particularly those with lower alkyl halides, e.g. methyl, ethyl, n-propyl or isopropyl chloride, bromide or iodide and the like, phenyl-lo wer a-lkyl halides,

eg. benzyl chloride, benzyl bromide, 2-phenylethyl b'romide and the like, di-lower alkyl sulfates, e.g. dimethyl sulfate, diethyl sulfate and the like, loweralkyl lower alkane sulfonates, elg. methyl or ethyl methane or. ethane sulfonate and the like, or lower alkyl mo-nocyclic carbocyclic aryl sulfonates, e.g. methyl p-to'luene sulfonate and the like. Also included as quaternary ammonium compounds are the quaternary ammonium hydroxides, and other quaternary ammonium salts having an anion other than a halogeno, sulfate or sulfonate ion. iMonoor polyquaternary ammonium compounds may be formed, depending on the conditions of the quaternization reaction.

The compounds of this invention have adrenolytic, antihypertensive, anti-inflammatory, diuretic, saliuretic, analgesic, and antifibrillatory properties and can be used accordingly.

Compounds of the present invention having adrenolytic effects are useful as vasodilators in peripheral vascular diseases, e.g. Reynauds disease, causalgia and the like, or to counteract the pronounced effects on the tissue of pressor substances, such as norepinephrine and the like; they are also useful as diagnostic tools to determine the proper functioning of the adrenal glands, due to their capability of suppressing the release of pressure substances, e.g. epinephrine, norepinephrine and the like, from normal functioning glands.

Compounds of this invention having antihypertensive properties are useful as hypotensive agent to lower the blood pressure in hypertensive conditions; they exert their hypotensive effects without causing tachycardia.

Compounds of this invention having anti-inflammatory properties, as demonstrated in the granuloma pouch test (Selye, Proc. Soc. Exp. Biol. & Med, vol. 82, p. 328 (1953), as modified by Robert et al., Acta Endocrinologica, vol. 25, p. 105 (1957)), the cotton pellet implant test (Meier et al., Experientia, vol. 6, p. 469 (1950)) or the pleural cavity inflammation test (Holtcamp, Fed. Proc., vol. 17, p. 379 (1958)), are useful as anti-inflammatory agents in place of corticoid steroids, e.g. cortisone, hydrocortisone and the like, for example, in the treatment of tissue intlammations, such as arthritic infiammatious and the like.

Compounds having diuretic and saliuretic properties are useful as diuretic and saliuretic agents to relieve conditions of excessive water and salt retention caused, for example, by kidney or heart ailments.

Compound of this invention having analgesic effects are useful as analgesic agents in raising the threshold of pain, as associated, for example, with arthritic conditions and the like.

Compounds of this invention having antifibrillatory effects are useful as antifibrillatory agents in the treatment of heart fibrillations, such as neurogenic or cardiogenic, auricular or ventricular fibrillation.

Especially useful are the compounds of the formula g2 JH(CH2)mN in which R has the previously-given meaning, i.e. stands for lower alkyl having preferably from one to four carbon atoms, the letter In stands for one of the integers 1 and 2, the radical R represents hydrogen or methyl, and each of the groups R,, and R stands for hydrogen, lower alkyl having preferably from one to four carbon atoms, lower alkoxy having prefer-ably from one to four carbon atoms, or halogeno having preferably an atomic weight between 19 and 80, both inclusive, and the acid addition salts, particularly the pharmaceutically acceptable, nontoxic acid addition salts, thereof.

Compounds With outstanding antihypertensive, as well as diuretic and saliuretic properties are those of the formula CHg-OHg in which R has the previously given meaning, and the acid addition salts, particularly the pharmaceutically acceptable, non-toxic acid addition salts, thereof.

Compounds with pronounced adrenolytic effects are those of the formula in which R has the previously-given meaning, and R is methyl, methoxy or chloro, or the acid addition salts, particularly the pharmaceutically acceptable, non-toxic acid addition salts thereof.

Strong anti-inflammatory effects are exhibited by the compounds of the formula in which R has the previously-given meaning, R i hydrogen, methyl, methoxy or chloro, R, is hydrogen or ralogeno, especially fiuoro or chloro, R is hydrogen or methyl, and the letter m stands for one of the integers 1 and 2, or acid addition salts, such as pharmaceutically acceptable, non-toxic acid addition salts, thereof; compounds of this type show anti-inflammatory effects, when given orally.

The new compounds of this invention are used in the form of compositions for enteral, e.g. oral, or parenteral administration, which contain the new compounds in admixture with a pharmaceutically acceptable, organic or inorganic, solid or liquid carrier. For making up the preparations, there are employed known carrier substances, such as Water, gelatine, lactose, starches, stearic acid, magnesium stearate, stearyl alcohol, talc, tragacanth, vegetable oils, benzyl alcohols, gums accacia, propylene glycol, polyalkylene glycols or any other carrier material suitable for such preparations. The latter are in solid form, e.g. capsules, tablets, dragees, suppositories and the like, or in liquid form, e.g. solutions, suspensions, emulsions and the like. If necessary, they contain auxiliary substances, such as preserving, stabilizing, wetting, emulsifying, coloring, flavoring agents and the like, salts for varying the osmotic pressure, buffers, etc. They may also contain, in combination, other useful substances.

The compounds of this invention are prepared according to known methods, for example, by reacting an N-monocyclic aryl-diaza-cycloalkane, in which the diazacycloalkane group has from six to eight ring members and its two nitrogen atoms are separated from one another by two to three carbon atoms, and monocyclic aryl has the above-given meaning, especially a compound of the formula in which Ar, Z and Z have the previously-given meaning, or a salt thereof, with a reactive ester of an x-lower alkoxy-x-monocyclic carbocyclic aryl-lower alkanol, in which lower alkoxy and monocyclic carbocyclic aryl substitute the same carbon atom and are separated from the esterified hydroxyl group by twoto four carbon atoms, and monocyclic carbocyclic aryl has the previously-given meaning, particularly with a compound of the formula in which R, Ph and the group of the formula (C,,H

have the previously-given meaning, and R is a reactive esterified hydroxyl group, and, if desired, converting a resulting salt into the free compound or into another salt, and/ or, if desired, converting a resulting compound into an N-oxide or a quaternary ammonium compound, and/or, if desired, converting a resulting compound or an N-oxide into a salt thereof, and/or, if desired, con

is verting a quaternary ammonium compound into another quaternary ammonium compound, and/or, if desired, separating a resulting mixture of isomers into the single isomers.

A salt of an N-monocyclic aryl-diaza-cycloalkane starting material is primarily a metal compound, such as an alkali metal, e.g. lithium, sodium, potassium and the like, compound thereof. Such compound is prepared according to known methods; for example, a solution of the N-monocyclic aryl-diaza-cycloalkane compound in a suitable solvent (the selection of which depends on the solubility of the starting material and/or the reactivity of the salt-forming reagent) or solvent mixture, is treated with an alkali metal, e.g. sodium and the like, with an alkali metal hydride or amide, e.g. lithium, sodium or potassium hydride or amide and the like, with an alkali metal carbonate, e.g. sodium carbonate, potassium carbonate and the like, or any other suitable salt-forming reagent, such as, for example, an alkali metal lower alkanolate and the like, if necessary, while cooling or heating, and/or in the atmosphere of an inert gas, e.g. nitrogen.

A reactive ester of an x-lower alkoxy-x-monocyclic carbocyclic aryl-lower alkanol is primarily an ester thereof with a strong inorganic acid, particularly a hydrohalic acid, e.g. hydrochloric, hydrobromic acid and the like, as well as sulfuric acid, or any other equivalent acid, or a strong organic sulfonic acid, e.g. methane sulfonic, p-toluene sulfonic acidcand the like. R in the above formula is primarily halogeno, particularly chloro, or bromo, as well as a sulfonyloxy group, e.g. methylsulfonyloxy, 4-methyl-phenyl-sulfonyloxy and the like. The preferred starting materials are represented by the x-lower alkoxy-x-monocyclic carbocyclic aryl-lower alkyl halides, in which lower alkyl separates lower alkoxy and the monocyclic carbocyclic aryl group from halogeno by two to four carbon atoms, such as the compounds of the formula 0-13 P h-- H- (CnHm) Hal in which Ph, R and the group of the formula (C,,H have the previously-given meaning, and Hal stands for halogeno, particularly halogeno having an atomic weight between 35 and 80, both inclusive, especially chloro, as well as bromo.

The reaction is carried out according to known methods. Thus, whenever the free N-monocyclic aryl-diaZa-cycloalkane is used, the acid generated by its reaction with the reactive ester of an x-lower alkoxy-x-monocyclic carbocyclic aryl-lower alkanol is neutralized by adding an excess of the N-monocyclic aryl-diaza-cycloalkane, or another base, e.g. sodium acetate, sodium carbonate, potassium carbonate and the like. The two starting materials may also be mixed together and the basic condensing reagent may then be added to bring about the reaction. The latter is preferably performed in the presence of a diluent (such as, for example, one of those used for the preparation of the metal compound), if necessary, while cooling or heating, in the atmosphere of an inert gas, e.g. nitrogen, and/ or in a closed vessel.

The starting materials used in the above reaction are known or may be prepared according to known methods.

The compounds of this invention may also be prepared by reacting an x-lower alkoxy-x-monocyclic carbocyclic aryl-lower alkyl-amine, in which lower alkoxy and monocyclic carbocyclic aryl substitute the same carbon atom and are separated from the amino group by two to four carbon atoms, and monocyclic carbocyclic aryl has the above given meaning, particularly a compound of the formula in which Ph, R and the group of the formula -(C,,H have the previously-given meaning, with an N,N-bis-(reactive esterified hydroxy-alkyl)-N-monocyclic aryl-amine,

in which the nitrogen is separated from the reactive esterilied hydroxyl groups by two to three carbon atoms, and monocyclic aryl has the above given meaning, particularly a compound of the formula Zn; in which Ar, Z and Z have the previously-given meaning, and each of the groups R and R stand for an esterified hydroxyl group, or a salt thereof, and, if desired, carrying out the optional steps.

In the above starting material, the reactive esterified hydroxyl groups R and R have the same meaning as R and represent primarily halogeno, having preferably an atomic weight between 35 and 80, both inclusive, i.e. chloro or bromo, as well as reactive organic sulfonyloxy groups. The reaction is carried out according to known methods, if necessary, at an increased temperature, in a closed vessel, in the atmosphere of an inert gas, e.g. nitrogen, and/ or in the presence of an acid neutralizing base.

The starting materials are known or may be prepared according to the known methods. For example, a reactive ester of an x-lower alkoxy-x-monocyclic carbocyclic aryl-lower alkanol, when reacted with ammonia or an equivalent reagent, such as an N-alkali metalphthalimide and then hydrazine, may be converted into the desired x-lower alkoxy-x-monocyclic carbocyclic aryl lower alkylamine.

A further process for the preparation of the compounds of this invention comprises reacting an N,N-di-(reactive esterified hydroxy-alkyl)-N- x-lower alkoxy-X-monocyclic carbocyclic aryl-lower alkoxy)-amine, in which alkyl separates the nitrogen atom from the reactive esterified hydroxyl groups by from two to three carbon atoms, and lower alkoxy and monocyclic carbocyclic aryl substitute the same carbon atom and are separated from the nitrogen atom by two to four carbon atoms, and in which monocyclic carbocyclic aryl has the above given meaning, particularly a compound of the formula in which Ph, R, Z Z R R and the group of the formula (C Hzn) have the previously-given meaning, or a salt thereof, with an N-monocyclic aryl-amine, in which monocyclic aryl has the previously-given meaning, particularly a compound of the formula ArNl-I in which Ar has the previously-given meaning, and, if desired, carrying out the optional steps.

The above reaction is carried out according to known methods, such as those mentioned hereinbefore. The starting material, i.e. an N,N-bis-(reactive esterified hydroxy-alky1)-N-(x-lower alkoxy-x-monocyclic carbocyclic aryl-lower alkyl)-amine, may be obtained, for example, by treating a reactive ester of an x-lower alkoxy-x-monocyclic carbocyclic aryl-lower alkanol, in which lower alkoxy and monocyclic carbocyclic aryl radical substitute the same carbon atom and are separated from the esterified hydroxyl group by two to four carbon atoms, and monocyclic carbocycli aryl has the previously-given meaning, with an N,N-bis-(hydroxy-alkyl)-amine, in which alkyl has two to seven carbon atoms separating nitrogen from the hydroxyl groups by two to three carbon atoms, and converting in a resulting N,N-bis-(hydroxyalkyl)-N-(x-lower alkyl-x-monocyclic carbocyclic aryllower alkyl)-amine, in which alkyl has from two to seven carbon atoms separating the nitrogen atom from the hydroxyl group by two to three carbon atoms, and lower alkyl and monocyclic carbocyclic aryl substitute the same carbon atom and are separated from the nitrogen atom by two to four carbon atoms, and monocyclic carbocyclic aryl has the previously-given meaning, the free hydroxyl groups into reactive esterified hydroxyl groups, such as halogeno, e.g. chloro and the like (for example, by treatment with a thionyl halide, e.g. thionyl chloride and the like, or a phosphorus halide, e.g. phosphorus tribromide and the like), or into reactive organic sulfonyloxy groups, e.g. methylsulfonyloxy, 4-methylphenyl-sulfonyloxy and the like (for example, by treatment with an organic sulfonic acid halide, e.g. methane sulfonic acid chloride, p-toluene sulfonyl chloride and the like).

The compounds of this invention are also prepared by converting in an N-(x-hydroxy-x-monocyclic carbocyclic aryl-lower alkyl)-N-monocyclic aryl-diaza-cycloalkane, in which hydroxyl and monocyclic carbocyclic aryl substitute the same carbon atom and are separated from the nitrogen atom of the diaza-cycloalkane portion by two to four carbon atoms, and in which the diaza-cycloalkane portion has from six to eight ring members and its two nitrogen atoms are separated from one another by two to three carbon atoms, and monocyclic carbocyclic aryl and monocyclic aryl have the previously-given meaning, particularly in a compound of the formula in which Ph, Z Z Ar and the group of the formula (C H n) have the previously-given meaning, or a salt thereof, the hydroxyl group into lower alkoxy, and, if desired, carrying out the optional steps.

The conversion of hydroxyl into lower alkoxy is carried out, for example, by treatment with a lower diazaalkane, preferably in the presence of a suitable Lewis acid, such as fluoboric acid, aluminum chloride, borontrifluoride etherate, an aluminum lower alkanolate, e.g. aluminum isopropanolate and the like, or any other suitable reagent. The conversion of hydroxyl into the desired lower alkoxy group is also carried out indirectly, for example, by converting the starting material into a metal compound, particularly into an alkali metal, e.g. sodium, potassium and the like, compound (for example, according to the previously-described process) and reacting the latter with a reactive ester of a lower alkanol, for example, a lower alkyl halide, e.g. chloride, bromide, iodide and the like. Furthermore, the free hydroxyl group of the starting material may be converted into a reactive esterified hydroxyl group, such as halogeno, e.g. chloro, bromo and the like, or an organic sulfonyloxy group, e.g. methylsulfonyloxy, p tolylsulfonyloxy, p-bromo-phenylsulfonyloxy, p-nitro-phenylsulfonyloxy, m-nitro-phenylsulfonyloxy and the like, according to the previously-described method. A resulting N-(x-reactive esterified hydroxy-x-monocyclic carbocyclic aryl-lower alkyl)-N- monocyclic aryl-diaza-cycloalkane is then reacted with a suitable reagent capable of replacing the reactive esterified hydroxyl group by the desired lower alkoxy group; halogeno in an N-(x-halogeno-x-monocyclic carbocyclic aryl-lower alkyl)-N'-mono-cyclic aryl-diaza-cyclo-alkane may be replaced by lower alkoxy by treating the intermediate with an alkali metal lower alkoxide, e.g. sodium or potassium rnethoxide, ethoxide, n-propoxide, isopropoxide, n-butoxide and the like, whereas the organic sulfonyloxy group in an N-(x-monocyclic carbocyclic aryl- X-organic sulfonyloxy-lower alkyl)-N-monocyclic aryldiaZa-cycloalkane may be exchanged for lower alkoxy by treatment of the intermediate compound with a lower alkanol, e.g. methanol, ethanol, n-propanol, isopropanol, n-butanol and the like, preferably in the presence of a suitable base, e.g. N,N-diethylamine, N,N,N-triethylamine, pyridine and the like, and, if necessary, at an elevated temperature, in a closed vessel and/or in the atmosphere of an inert gas.

The starting materials used in the above procedure are prepared according to known methods, for example, by reducing in an N-(x-monocyclic carbocyclic aryl-x-oxolower alkyl)-N-mono-cyclic aryl-diaza-cycloalkane the 0x0 into a hydroxyl group by reduction, for example, by treatment with sodium borohydride and the like.

The compounds of this invention, in which the a-group of the lower alkyl portion is a methylene group of the formula CH may also be prepared by converting in an N-(x-lower alkoxy-x-monocyclic carbocyclic aryl lower alkanoyl)-N-monocyclic aryl-diaza-cycloalkane or in an N-(x-lower alkoxy-x-monocyclic carbocyclic aryl-lower thioalkanoyl)-N-monocyclic carbocyclic aryldiaza-cycloalkane, in which lower alkoxy and monocyclic carbocyclic aryl group substitute the same carbon atoms and are separated from the carbonyl or thiocarbonyl group by one to three carbon atoms, and in which the diaZa-cycloalkane portion has from six to eight ring members, and its two nitrogen atoms are separated from one another by two to three carbon atoms, and monocyclic carbocyclic aryl and monocyclic aryl have the previouslygiven meaning, particularly in a compound of the formula Ph-(JH-x-e-n l IAr Z2- in which Ph, R, Z Z and Ar have the previously-given meaning, A is a direct bond or an alkylene radical having from one to five carbon atoms and separating the carbon atom carrying lower alkoxy and monocyclic carbocyclic aryl from the carbonyl or thiocarbonyl group by one to two carbon atoms, and the group X is oxygen or sulfur, the carbonyl group or the thiocarbonyl group into methylene, and, if desired, carrying out the optional steps.

The conversion of a carbonyl group into a methylene radical is carried out according to known procedures, for example, by treatment with a suitable aluminum hydride reagent, e.g. lithium aluminum hydride and the like, in the presence of a suitable solvent, e.g. diethyl ether, tetrahydrofuran and the like, or by any other suitable reduction method, such as hydrogen in the presence of certain catalysts, such as copper-chromium catalysts and the like, or by electroyltic reduction. A thiocarbonyl group may be converted into the methylene group, for example, by treatment with a suitable desulfurizing reagent, e.g. Raney nickel and the like.

The starting materials used in the above procedure may be prepared according to know methods, for example, by reacting an N-monocyclic aryl-diaza-cycloalkane with an x-lower alkoxy-x-monocyclic carbocyclic aryl-lower alkanoic acid halide, e.g. chloride and the like, and, if desired, converting in a resulting N-(x-lower alkoxy-xrnonocyclic carbocyclic aryl-lower alkanoyl)-N'-monocyclic aryl-diaza-cycloalkane the carbonyl group into thiocarbonyl, for example, by treatment with phosphorus pentasulfide and the like.

A resulting salt may be converted into the free compound, for example, by treatment with a base, such as a metal hydroxide, e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide and the like, a metal carbonate, e.g. sodium, potasium or calcium carbonate or hydrogen carbonate and the like, ammonia and the like, or with a hydroxyl ion exchange preparation or any other suitable reagent.

A resulting salt may be converted into another salt; for example, a salt with an inorganic acid may be treated with a suitable metal, e.g. sodium, barium, silver and the like, salt of an acid in the presence of an appropriate solvent, for example, a solvent, in which a resulting inorganic compound is insoluble and is thus removed from the reaction medium, or by treating a salt with an anion exchange preparation or any other suitable reagent.

A free base may be converted into its acid addition salt by reacting it with an acid, such as one of the inorganic or organic acids mentioned before, for example, by treat crystallization.

The compounds of the present invention form N-oxides, which are prepared according to known methods, for example, by reacting a resulting compound, prefer-ably a solution thereof in an inert solvent, with an N-oxidizing reagent, such as, for example, hydrogen peroxide, ozone, persulfuric acid, or an organic peracid, such as an organic percarboxylic acid, erg. peracetic, perbenzoic, monoperphthalic acid and the like, or an organic persulfonic acid, e.g. p-toluene persulfonic acid and the like. A resulting N-oxide may be converted into its acid addition salts according to the above methods.

Quaternary ammonium derivatives of the compounds of this invention are obtained, for example, by reacting the free compound with an ester formed by an alcohol and a strong inorganic or organic acid, suchas one of those previously mentioned. The quaternizing reaction may be performed in the presence or absence of a suitable solvent, if necessary, While cooling or at an elevated temperature, at atmospheric pressure or in a closed vessel under increased pressure, and/ or in the atmosphere of an inert gas, e.g. nitrogen.

Resulting quaternary ammonium compounds may be converted into other quaternary ammonium compounds, such as the corresponding quaternary ammonium hydroxides, for example, by reacting a quaternary ammonium halide with silver oxide, or a quaternary ammonium sulfate with barium hydroxide, by treating a quaternary ammonium salt with an anion exchange preparation, by electrodialysis and the like. From a resulting quaternary ammonium hydroxide, there may be prepared a quaternary ammonium salt by reaction with an acid or with a lower alkyl sulfate, e.g. methyl sulfate, ethyl sulfate and the like. A quaternary ammonium salt may also be converted directly into another quaternary ammonium salt without the formation of an intermediary quaternary ammonium hydroxide; for example, a quaternary ammonium iodide may be reacted with freshly prepared silver chloride or with hydrogen chloride in anhydrous methanol to yield the quaternary ammonium chloride, or a quaternary ammonium salt may be treated with a suitable anion exchange preparation and converted into another quaternary ammonium salt. Quaternary ammonium compounds may be isolated in the form of hydrates or may contain solvent of crystallization.

A resulting mixture of isomers may be separated into single isomers. For example, a mixture of diastereoisomeric compounds may be separated into the individual racemic compounds on the basis of physico-chemical differences, such as solubility, for example, by fractional crystallization and the like. Racemates may be resolved into the optically active dand l-forms according to known resolution procedures, for example, reacting the free racemic compound, preferably in the presence of a suitable solvent, with one of the optically active forms of an acid having an asymmetric carbon atom or a solution thereof. Especially useful as optically active forms of salt-forming acids having an asymmetric carbon atom are D-tart-aric (l-tartaric) and L-tart'aric (d-tartaric) acid, as well as the optically active forms of malic, mandelic, camphor -sulfonic, quinic acid and the like. The resulting salts of the antipodes with the optically active acid are separated on the basis of physico-chemical differences, particularly different solubilitics, and, if desired, converted into the free and optically active compounds according to the above procedure. An optically active base may be converted into another acid addition salt, an N-oxide, an acid addition salt of an N-oxide or a 10 quaternary ammonium compound according to the abovedescribed methods.

The invention also comprises any modification of the process wherein a compound obtainable as an intermediate at any stage of the process is used as starting material and the remaining step(s) of the process is (are) carried out, as well as any new intermediates.

In the process of this invention such starting materials are preferably used which lead to final products mentioned inthe beginning as preferred embodiments of the invention.

This is a continuation-in-part application of our application Serial No. 253,247, filed January 23, 1963 (now abandoned), which in turn is a continuation-in-part application of our application Serial No. 238,027, filed N0- vember 15, 1962 (now abandoned), which in turn is a continuationin-part application of our application Serial No. 168,544, filed January 24, 1962 (now abandoned), which in turn is, a continuation-in-part application of our application Serial No. 96,691, filed March 20, 1961 (now abandoned). i

i The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon.

Example 1 To a solution of 8.8 g. of Z-methyl-l-phenyl-piperazine in 50 ml. of toluene is added 2.4 g. of a mineral oil sus pension of sodium hydride (of 53 percent strength); the mixture is refluxed for two hours, and is then treated with 11.6 g. of 3-ethoxy-3-(4-methyl-phenyl)-propyl chloride. Refluxing is continued overnight; the inorganic material is filtered off, the filtrate is evaporated under reduced pres sure, and the residue is distilled to yield 1--[3-ethoxy-3(4- methyl-phenyl)-propyl]-3-methyl-4-phenyl-piperazine of the formula which boils at 182-184/ 0.2 mm.

The dihydrochloride of 1-[3-ethoxy-3-(4-methyl-phenyl -propyl] -3 -methyl-4-phenyl-piperazine, M.P. 190-192 is prepared by treating a solution of the free base in ethanol with a saturated solution of hydrogen chloride in ethanol and recrystallizing the resulting salt from ethanol.

Other compounds prepared according to the above procedure are, for example:

drochloride of which melts at 165 (after recrystallization from acetone);

1 [3 methoxy-3-(4-methyl-phenyl)-propyl]-3-methyl- 4-phenyl-piperazine, B.P. 176178/ 0.1 mm., the hydrochloride of which melts at 197-198 (after recrystallization from acetone);

'1 [3-methoxy-3-(4-rnethyl-phenyl)-propyl]-4-(2-rnethyl phenyl)-piperazine, B.P. l182/0.12 mm., the hydrochloride of which melts at 163 (after recrystallization from acetone);

' 4 (2-chloro-phenyl)-1-[3-methoxy-3-(4-rnethyl-phenyl)- 1 [3-methoxy-3-(4-methyl-phenyl)-propyl]-4-(3-methylphenyl)-piperazine, B.P. 174l78/0.07 mm, the dihydrochloride of which melts at 155 (after recrystallization from acetone);

1 [3 isopropyloxy-3-(4-methyl-phenyl)-propyl]-4-(2- methyl-phenyl)-piperazine, B.P. 176-180/ 0.04 mm., the dihydrochloride of which melts at 171173 (after recrystallization from isopropanol);

4 (2 chloro-phenyl)-l-[3-isopropyloxy-3-(4-methylphenyl)-propyl]-piperazine, B.P. 194200/0.04 mm., the hydrochloride of which melts at 159 (after recrystallization from acetone);

1 [3 isopropyloxy-3-(4-methyl-phenyl)-propylJ-4-(4- methyl-phenyl)-piperazine, B.P. 190-192/0.09 mm, the dihydrochloride of which melts at 173 (after recrystallization from acetone);

4 (2 chloro-phenyl)-l-(3-ethoxy-3-phenyl-propyl)-piperazine, B.P. 176178/ 0.03 mm., the dihydrochloride of which melts at 141143 (after recrystallization from a mixture of acetone and diethyl ether);

1 [3 methoxy-3-(4-methyl-phenyl)-propyl]-4-(4-methyl-phenyl)-piperazine, B.P. 208212/0.09 mm., the dihydrochloride of which melts at 192 (after recrystallization from isopropanol);

4 (4 chloro-phenyl)-1-(3-ethoxy-3-phenyl-propyl)-piperazine, B.P. 23 8-240/ 0.08 mm., the dihydroehloride of which melts at 155 (after recrystallization from isopropanol);

4 (2 methyl-phenyl)-1-(3-ethoxy-3-phenyl-propyl)-piperazine, B.P. l80l82/0.2 mm., the dihydrochloride of which melts at 150-154 (after recrystallization from ethanol);

4 (4 methyl-phenyl)-1-(3-ethoxy-3-phenyl-propyl)-piperazine, B.P. 180-183/ 0.2 mm, the dihydrochloride of which melts at 200 (after recrystallization from ethanol);

4 (4 methoxy-phenyl)-1-(3-ethoxy-3-phenyl-propyl)- piperazine, the dihydrochloride of which melts at 210- 211 (after recrystallization from ethanol);

as well as 1-[3-(4-methoxy-phenyl)-3-n-propyloxy-propyl] 3-methyl-4-phenyl-piperazine, 1-[3-ethoxy-3-(4-trifluoromethylphenyl) propyl]-3-methyl-4-phenyl-piperazine and the like.

Example 2 To a solution of 8.1 g. of l-phenyl-piperazine in 50 ml. of toluene is added 2.4 g. of a sodium hydride suspension in mineral oil (of 53 percent strength); the reaction mixture is refluxed for 2 /2 hours and is then treated with 9.9 g. of 3-ethoxy-3-phenyl-propyl chloride. After refluxing for an additional four hours, the desired 1-(3- ethoxy-3-phenyl-propyl)-4-phenyl-piperazine of the formula 53 percent strength) in 50 ml. of toluene is refluxed for six hours and then treated with 8.0 g. of 3-ethoxy-3-(4- 112 methyl-phenyD-propyl chloride; the reaction mixture is worked up as described in Example 1 to yield the 1-[3- ethoxy-3- 4-methyl-phenyl -propyl] -4- 2-pyridyl) -piperazine of the formula which boils at 162-163/ 0.25 mm., and is converted into its trihydrochloride, M.P. 194-195 Example 4 To a solution of 7.0 g. of l-phenyl-piperazine in ml. of toluene is added 2.3 g. of a 53 percent suspension of sodium hydride in mineral oil. The reaction mixture is refluxed for 2 /2 hours, then cooled to room temperature, treated with 9.0 g. of 3-(4-chloro-phenyl)-3-ethoxypropyl chloride, and refluxed for an additional 36 hours. After standing overnight, the inorganic material is filtered off, the filtrate is evaporated to dryness under reduced pressure and the residue is distilled to yield the 1-[3-(4 chloro-phenyl)-3-ethoxy-propyl]-4-phenyl piperazine of the formula which is collected at 168/0.1 mm. and dissolved in 10 ml. of ethanol. The solution is treated with 10 ml. of ethanol saturated with hydrogen chloride and the desired 1- [3- (4-chloro-phenyl) -3-ethoxy-propyl] -4-phenyl-piperazine dihydrochloride precipitates and is recrystallized from ethanol, M.P. 208.

Example 5 A mixture of 7.0 g. of l-phenyl-piperazine and 4.56 g. of sodium carbonate in 100 ml. of ethanol is refluxed for four hours, then cooled to room temperature and treated with 9.0 g. of 3-(4-chloro-phenyl)-3-ethoxy-propyl chloride. The reaction mixture is refluxed for an additional 18 hours and worked up as described in Example 4 to yield the 1-[3-(4-chloro-phenyl)-3-ethoxy-propyl1-4- phenyl-piperazine, collected at 196-2l2/0.070.09 mm., which is converted into its dihydrochloride M.P. 199, and is identical with the product obtained according to the procedure described in Example 4.

Example 6 To a solution of 24.0 g. of Z-methyl-l-phenyl-piperazine in 250 ml. of toluene is added 7.5 g. of a 53 percent suspension of sodium hydride in mineral oil; the reactive mixture is refluxed for four hours, cooled to room temperature and treated with 32.6 g. of 3-(4-chloro-phenyl)- 3-ethoxy-propyl chloride. After refluxing for an additional 18 hours and stirring at room temperature for 2 /2 days, the solid material is filtered otf, the filtrate is concentrated under reduced pressure and the residue is distilled to yield the 1 [3 (4 chloro-phenyl) 3 ethoxypropyl]-3-methyl-4-phenyl-piperazine of the formula which is collected at 206208/ 0.07 mm., and converted into its dihydrochloride, M.P. 192 (after three recrystallizations from acetone).

Example 7 A mixture of 6.7 g. of 1-(2-methyl-phenyl)-piperazine and 4.0 g. of sodium carbonate in ml. of ethanol is refluxed for four hours, then cooled to room temperature and treated with 8.0 g. of 3ethoxy-3-(4-methylpheny1)-propyl chloride; the reaction mixture is heated to reflux for 18 /2 hours, filtered, and the filtrate is evapo- 5. rated to dryness under reduced pressure. The residue is distilled to yield the 1-[3-ethoxy-3-(4-methyl-phenyl)- propyl]-4-(2-methyl-phenyl)-piperazine of the formula which is collected at 186/0.05 mm. and converted into its dihydrochloride by treating an ethanol solution of the free base with ethanolic hydrogen chloride; the salt melts at 164 166", after recrystallization from ethanol.

Example 8 methyl-phenyl)-propyl]-piperazine of the formula which is collected at 184186/0.04-0.05 mm, and converted into its dihydrochloride, M.P. 150-152 (after recrystallization from acetone).

Example 9 A mixture of 7.2 g. of 1-(Z-methoxy-phenyl)-piperazine and 4.0 g. of sodium carbonate in 150 ml. of ethanol is refluxed for four hours, cooled and then treated with 8.0 g. of 3-ethoxy-3-(4-rnethyl-phenyl)-propyl chloride;

the reaction mixture is heated for an additional 18 hours and worked up as described in Example 4. The resulting 1 [3 ethoxy 3 (4 methyl phenyl) propyl]- 4-(2-methoxy-phenyl)-piperazine of the formula O-C H CHZCH nao-gen-orrrom-Ng N C Hr C H2 0011:; is collected at 222-224/O.14mm. and converted into its dihydrochloride, MP. 186 (after recrystallization from acetone).

Example 10 A mixture of 7.5 g. of 1-(3-chloro-phenyl)-piperazine and 4.0 g. of sodium carbonate in 125 ml. of ethanol is refluxed for four hours, cooled to room temperature and treated with 8.0 g. of 3-ethoxy-3-(4-methyl-phenyl)- propyl chloride; the reaction mixture is heated for 18 hours and then worked up as described in Example 4 to yield the 4-(3-chloro-phenyl)-1-[3-ethoxy-3-(4- methyl-phenyl)-propyl]-piperazine of the formula which is collected at 208210/O.G6 mm. and converted into its hydrochloride, M.P. 168470 (after recrystallization from acetone).

Example 11 14 is dissolved in ethanol, and the solution is heated with ethanol saturated with hydrogen chloride and diluted with diethyl ether. The precipitate is filtered off and recrystallized from acetone to yield the 4-(2-methoxyphenyl) 1 [3 methoxy 3 (4 methyl phenyl)- propyl]-piperazine dihydrochloride of the formula O-CH3 GHQ-CH2 which melts at 175-477".

Example 12 A mixture of 11.8 g. of 1-(4-chloro-phenyl)-piperazine and 6.5 g. of sodium carbonate in 250' ml. of ethanol is refluxed for four hours and then cooled to room temperature; 14.0 g. of 3-(4-chloro-phenyl)-3-ethoxy-propyl chloride is added and refluxing is continued for an additional 18 hours. The reaction mixture is worked up as described in Example 4; the desired 4-(4-chlorophenyl) 1 [3 (4 chloro phenyl) 3 ethoxyropyH-piperazine of the formula C IIr- C 112 is collected at 214216/ 0.11 mm. and converted into its hydrochloride, M.P. 188 (after recrystallization from acetone).

Other compounds, which may be prepared according to the above procedure are, for example:

CHg-CHg I 1 [3 4 chloro phenyl) 3 ethoxy propyl] 4 (3- methoxy-phenyl)-piperazine, 8.1 204-206/0.12 mm., the dihydrochloride of which melts at (after re crystallization from ethanol);

1 [3 (4 chloro phenyl) 3 methoxy propyl] 3- methyl 4 phenyl piperazine, Bl. -178"./ 0.05 mm, the dihydrochloride of which melts at 184;

1 [3 (4 chloro phenyl) 3 ethoxy propyl] 4- (4 methyl phenyl) piperazine, Bl. 196200/ 0.04 mm., the dihydrochloride of which melts at 197 (after recrystallization from isopropanol);

1 [3 (4 chloro phenyl) 3 isopropyloxy propyll- 4 phenyl piperazine, B.P. l98-200./ 0.09 mm., the dihydrochloride of which melts at 200 (after recrystallization from ethanol);

1 [3 (4 chloro phenyl) 3 methoxy propyl] 4- phenyl-piperazine, Bl. 192-194/0.08 mm., the dihydrochloride of which melts at 215 (after recrystallization from acetone);

1 [3 (4 chloro phenyl) 3 methoxy propyl] 4- (4 methyl phenyl) piperazine, Bl. 186-190/ 0.09 mm., the dihydrochloride of which melts at 195 (after recrystallization from actone);

1 [3 (4 chloro phenyl) 3 methoxy propyl] 4- (2 methyl phenyl) piperazine, B.P. 208210/0.17 mm., the dihydrochloride of which melts at 165 (after recrystallization from acetone);

1 [3 (4 chloro phenyl) 3 ethoxy propyl] 4- (3 methyl phenyl) piperazine, B.P. 182/0.04 mm., the dihydrochloride of which melts at 173 (after recrystallization from ethanol);

as well as 1 [3-ethoxy 3 (4-fluoro-phenyl)-propyl]-3- methyl-4-phenyl-piperazine, 1- [3 3-bromo-phenyl -3-ethoxy-propyl] 3-methyl-4-phenyl-piperazine, 4 (Z-chloroazine and the like.

Example 13 To a solution of 10.6 g. of 1-(4-methyl-pl1enyl)-piperazine in 250 ml. of ethanol is added 6.4 g. of sodium carbonate; the mixture is then refluxed for four hours, cooled to room temperature, treated with 6.4 g. of 3-ethoxy-3-(4-methyl-phenyl) propyl chloride and again heat- 15 ed to reflux for 18 hours. The solid material is filtered off, the filtrate is evaporate to dryness and the residue is extracted with diethyl ether. The organic solution is evaporated to dryness, and the residue is distilled to yield the 1 [3 ethoxy 3 (4 methyl phenyl) propylJ- 4-(4-methyl-phenyl)-piperazine of the formula which is collected at 192196/ 0.011 mm., and converted into its dihydrochloride, M.P. 194195 (after recrystallization from acetone).

The 1 [3 isopropyloxy 3 (4 methyl phenyl)- propyl]-4-(2-methoxy-phenyl)-piperazine is prepared according to the above procedure, collected at 215 /O.26 mm., and converted into its dihydrochloride, Ml. 179 (after recrystallization from isopropanol).

Example 14 A mixture of 3.6 g. of 1-(4-chloro-phenyl)-piperazine and 1.65 g. of sodium carbonate in 150 ml. of ethanol is refluxed for four hours, cooled and treated with 3.32 g. of 3-ethoxy-3-(4-methyl-phenyl)-propyl chloride. The reaction mixture is refluxed for 18 hours, filtered and evaporated to dryness; the residue is dissolved in percent aqueous hydrochloric acid, and, upon adding diethyl ether, an oil precipitates. The liquids are decanted, and the residue is triturated wtih diethyl ether. The desired 4 (4 chloro phenyl) 1 [3 ethoxy 3 (4 methyl phenyl) propyl] piperazine hydrochloride of the formula solidifies and is recrystallized from acetone, MP. 174 176.

Example 15 To a solution of 10.6 g. of 1-(2-methyl-phenyl)-piperazine in 250 ml. of ethanol is added 6.4 g. of sodium carbonate; the reaction mixture is refluxed for four hours, cooled and treated with 14.0 g. of 3-(4-chloro-phenyl)- 3-ethoxy-propyl chloride and then refluxed for 18 hours. After cooling and filtering, the filtrate is evaporated under reduced pressure; the residue is extracted with diethyl ether, the organic solution is dried and evaporated, and the oily residue is distilled to yield the 1-[3-(4-chlorophenyl) 3 ethoxy propyl] 4 (2 methyl phenyl)- piperazine of the formula which is collected at 198202/0.16 mm., and converted into the dihydrochloride, M.P. 184 (after recrystallization from acetone).

Example 16 To a solution of 11.8 g. of l-(2-chloro-phenyl)-pipera zine in 250 ml. of ethanol is added 6.4 g. of sodium carbonate; the reaction mixture is refluxed for four hours, then cooled to room temperature and treated with 14.0 g. of 3-(4-chloro-phenyl)-3-ethoxy-propyl chloride. After refluxing for 18 hours and filtering, the solution is taken to dryness under reduced pressure and the residue is distilled. The desired 4-(2-cl1loro-pl1enyl)-1-[3-(4-chlorophenyl)-3-ethoxy-propyl]-piperazine of the formula is collected as a yellow oil, Bl. 210 212/0.07 nun, and

1'3 converted into its dihydrochloride by dissolving the free base in ethanol, adding ethanolic hydrogen chloride and precipitating the salt, which melts at 1 20 after recrystallization from acetone.

The 4-(3-chloro-phenyl) 1 [3-(4-chloro-phenyl)-3- ethoxy-propyl]-piperazine, which is prepared according to the above procedure, is collected at 206208/0.06 mm., and converted into its hydrochloride, IVLP. 169 (after recrystallization from isopropanol).

Example 17 A mixture of 3.0 g. of l-phenyl-piperazine and 2.0 g. of sodium carbonate in ethanol is refluxed for four hours; after cooling, it is treated with 4.3 g. of 3-(2-chlorophenyl)-3-ethoxy-propyl chloride and refluxing is continued for 18 hours. The reaction mixture is worked up as described in Example 16 and yields the l-[3-(2-chlorophenyl)-3-ethoxy-propyl]-4-phenyl-piperazine of the formula I Cm-om 01 which is collected at l82-184/0.08 mm., and converted into the dihydrochloride hemihydrate, MP. 170 after recrystallization from isopropanol.

Example 18 A mixture of 21.0 g. of l-phenyl-piperazine, 13.7 g. of sodium carbonate and 29.0 g. of 3-(4-chloro-phenyl)-3- ethoxy-propyl chloride in 200 ml. of ethanol is refluxed for 19 hours and then cooled to room temperature. After filtering, the filtrate is evaporated under reduced pressure and the residue is distilled to yield the 1-[3-(4-chlorophenyl)-3-ethoxy-propyl]-4-phenyl-piperazine, which is collected at l96208/0.06 mm., and converted into its dihydrochloride, MP. 201-203 (after recrystallization from ethanol). The compound is identical with the one obtained according to the procedure of Example 5.

The 1 [3-ethoxy 3-(4 methyl-phenyl)-propyl]-4- phenyl 1,4-diazacycloheptane, 1-(3-isopropyloxy-3-phenyl-propyl)-5phenyl-1,5-diazacycl0-octane, l-[3-ethoxy-3- (2,4-dimethyl-phenyl -propyl] -4- 4-chloro-phenyl -p1perazine, 2,6 dimethyl-4-(3-methoxy-3-phenyl-propyl)-lphenyl-piperazine and the like, may be prepared according to one of the above-described procedures, for example, by reacting the sodium salt of 1-phenyl-l,4-diazacycloheptane, l-phenyl 1,5 diazacyclo-octane, 1-(4-chlorophenyl)-piperazine, 2,6-dimethyl-l-phenyl piperazine and A mixture of 21.3 g. of 3-(4-chloro-phenyl)-3-ethoxypropyl-amine and 25.2 g. of N,N-di-(2-chloroethyl)-N- (2-chloro-phenyl)-amine in 100 ml. of methanol is refluxed in the presence of an excess of potassium carbonate for fifteen hours while stirring. The solid material is filtered off, the filtrate is concentrated under reduced pressure, and the residue is distilled to yield the 4-(2-chlorophenyl) 1-[3-(4-chloro-phenyl)-3-ethoxypropyl]-piperazine, which is collected at 2l0212/ 0.07 mm., and is converted into its dihydrochloride, M.P.

The starting material used in the above procedure 1s prepared as follows: A mixture of 50.0 g. of 3-(4-chlorophenyl)-3-ethoxy-propyl chloride and 44.0 g. of potassium phthalimide in 80 ml. of N,N-dimethylformamide is refluxed for two hours in the presence of a few crystals of potassium iodide as a catalyst. The hot solution is poured onto 200 g. of crushed ice; the organic material is extracted with chloroform, and the extract is washed with a l N aqueous solution of potassium hydroxide, 0.5 N

aqueous hydrochloric acid and water; After drying over sodium sulfate, the organic solution is concentrated to dryness under reduced pressure. The residue is treated with 200 ml. of methanol containing 20 ml. of hydrazine hydrate (99l00%) and refluxed for two hours. The solution is cooled, acidified with concentrated hydrochloric acid and again refluxed thirty minutes. After filtration, it is taken to dryness under reduced pressure, and the residue is dissolved in a minimum amount of water. The aqueous solution is made strongly alkaline with a 50 percent solution of potassium hydroxide, salted with potassium carbonate and extracted with diethyl ether. The organic extract is dried and concentrated under reduced pressure to yield the 3-(4-chloro-phenyl)-3-etnoxypropyl-amine, which is used in the subsequent step without further purification.

The N,N-di- 2-chloroethyl) -N- (2-chloro-phenyl-arnine used in the above procedure is prepared by heating a mixture of 2-chloro-aniline and ethylene oxide in a sealed tube and converting in a resulting N-(Z-chloro-phenyD- N,N-di-(2-hydroxyethyl)-amine, the hydroxyl groups into chloro by treatment with thionyl chloride.

Example 20 A mixture of 33.8 g. of N,N-di-(2-chloroethyl)-N-[3- (4-chloro-phenyl)-3-ethoxy-propyl]-amine and 1 2.8 g. of 4-chloroaniline in 100 ml. of methanol is refluxed in the presence of an excess of sodium carbonate for fifteen hours while stirring. The solid material is filtered off, the filtrate is evaporated to dryness, and the residue is distilled to yield the 4-(4-chloro-phenyl)-1-[3-(4-chloro-phenyl)- 3-ethoxy-propyl]-piperazine, which is collected at 214- 216/ 0.11 mm. and converted into its hydrochloride, M.P. 188.

The starting material used in the above procedure is prepared as follows: A mixture of 21.3 g. of 3-(4-chlorophenyl)-3-ethoxy-propyl-amine and 9.0 g. of ethylene oxide is heated in a sealed tube at 90-150 for sixteen hours. The content of the tube is extracted with ethanol,

and the organic solution is carefully concentrated under 1 reduced pressure to yield the N-[3-(4-chloro-phenyl)-3- ethoxy-propyl] -N,N-di- (2-hydroxyethyl -amine.

The latter compound may also be prepared as follows: A mixture of 53.0 g. of 3-(4-chloro-phenyl)-3-ethoxypropyl-amine and 100.0 g. of ethylene chlorohydrin in 250 ml. of water containing 35.0 g. of calcium carbonate is refluxed overnight while stirring. The hot mixture is filtered, the filtrate is saturated with sodium chloride, cooled and extracted with diethyl ether. The organic solution is concentrated under reduced pressure to yield the N [3-(4-chloro-phenyl) -3-ethoxy-propyl] -\l,N-di-(2- hydroxy-ethyl) -amir1e.

To a suspension of 25.0 g. of powdered phosphorus pentachloride in 100 ml. of dry chloroform is added 30.2 g. of N-[3(4-chloro-phenyl)-3-ethoxy-propyl]-N,N-di- (2-hydroxyethyl)-amine while cooling. After refluxing for one hour, the resulting solution is poured onto ice, the chloroform layer is separated, dried and concentrated under reduced pressure to yield the N,N-di-(2-chloroethyl) N-[3-(4-chloro-phenyl)-3-ethoxy-propyl]-amine. The latter may also be prepared by reacting the N-[3-(4- chloro-phenyl) 3 ethoxy-propyl]-N,N-di-(2-hydroxyethyl)-amine with about 1.2 moles of phosphorus oxychloride in benzene or about 1.4 moles of tbionyl chloride in benzene at Example 21 A mixture of 9.65 g. of 3-ethoxy-3-(4-methyl-phenyl)- propyl-ann'ne and 11.6 g. of N,N-di-(2-chloroethyl)-N- (2-methyl-phenyl)-amine in 50 ml. of methanol is refluxed in the presence of an excess of potassium car bonate for fifteen hours while stirring. The precipitate is filtered off, the filtrate is concentrated under reduced pressure, and the residue is distilled to yield the [3- ethoxy 3 (4 methyl phenyl) propyl] 4 .(2

methyl phenyl) piperazine, which is collected at 186/ 0.05 mm., and is converted into its dihydrochloride M.P. 164-166". v

The starting material used in the above procedure is prepared as follows: A mixture of 45.0 g. of 3-ethoxy 3 (4 methyl phenyl) propyl chloride and 44.0 g. of potassium phthalimide in 80 ml. of N,N-dimethylformamide is heated to reflux for two hours in the presence of a few crystals of potassium iodide as the catalyst. The hot solution is poured onto 200 g. of crushed ice, and the organic material is extracted with chloroform. The extract is washed with a 1 N aqueous solution of potassium hydroxide, 0.5 N aqueous hydrochloric acid and water, then dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue is treated with 200 ml. of methanol containing 20 ml. of hydrazine hydrate (99100%) and the mixture is refluxed for two hours. The solution is cooled, acidified with concentrated hydrochloric acid and again refluxed for thirty minutes. The reaction mixture is filtered, the filtrate is taken to dryness under reduced pressure, and the residue is dissolved in a minimum amount of water. The aqueous solution is made strongly alkaline with a 50 percent solution of potassium hydroxide, salted with potassium carbonate and extracted with diethyl ether. The organicextract is dried and concentrated under reduced pressure to yield the 3-ethoxy-3-(4-methyhphenyl) -propylamine, which is used in the subsequent step without further purification.

The N,N di (2 chloroethyl) N (2 methyl phenyl)-amine used in the above procedure is prepared by heating a mixture of o-toluidine and ethylene oxide is a sealed tube and converting in the resulting N,N-di- (2 hydroxyethyl) N (2 methyl phenyl) amine, the hydroxyl groups into chloro by treatment with thionyl chloride.

Example 22 A mixture of 15.9 g. of N,N-di-(2-ch1oroethyl-N- [3 ethoxy 3 (4 methyl phenyl) propyl] amine and 12.3 g. of Z-methoxyaniline in 50 ml. of methanol is refluxed in the presence of an excess of sodium carbonate for fifteen hours while stirring. The solid material is filtered off, the filtrate is evaporated to dryness, and the residue is distilled to yield the 1-[3-ethoxy-3-(4- methyl phenyl) propyl] 4 (2 methoxy phenyl) piperazine, which is collected at 222224/ 0.14 mm. and converted into its hydrochloride, M.P. 186.

The starting material used in the above procedure is prepared as follows: A mixture of 19.4 g. of 3-ethoxy- 3 (4 methyl phenyl) propyl amine and 9.0 g. of ethylene oxide is heated ina sealed tube at about 120 for sixteen hours. The reaction mixture is extracted with ethanol, and the ethanol solution is carefully concentrated under reduced pressure to yield the N,N-di-(2- hydroxyethyl) N,N [3 ethoxy 3 (4 methyl phenyl) -propyl] -amine.

To a suspension of 25.0 g. of powdered phosphorus pentachloride in ml. of dry chloroform is added 29.8 g. of N.N di (2 hydroxyethyl) N [3 ethoxy 3 (4 methyl phenyl) propyl] amine While cooling. After refluxing for one hour, the resulting solution is poured onto ice, the chloroform layer is separated, dried and concentrated under reduced pressure to yield the N,N di (2 chloroethyl) N [3 ethoxy 3 (4methyl-phenyl -pr-opyl] -amine.

Example 23 A mixture of 10.05 g. of 1-(2-methoxy-phenyl)-piperazine and 11.5 g. of 2-(4-chloro-phenyl)-2-ethoxy-ethyl chloride in 200 ml. of butanol is refluxed for .24 hours in the presence of 40.0 g. of sodium carbonate while stirring. The'inorganic material is filtered off, the filtrate is concentrated to dryness and the residue is dis- 19 tilled to yield the 1-[2-(4-chloro-phenyl)-2-ethoxy-ethyl]- 4-(2-methoxy-phenyl)-piperazine of the formula C H CHFOHI which is collected at 190200/ 0.3 mm.

A solution of the free base in ethanol is treated with a saturated solution of hydrogen chloride in ethanol and diluted with diethyl ether; the resulting 1-[2-(4- chloro phenyl) 2 ethoxy ethyl] 4 (2 methoxy phenyl)-piperazine dihydrochloride melts at 229231 after recrystallization from isopropanol.

The 2 (4 chloro phenyl) 2 ethoxy ethyl chloride starting material used in the above example is prepared as follows: To a mixture of 8.16 g. of magnesium in 75 ml. of diethyl ether is added a small portion of the total of 76.4 g. of 4-chloro-bromobenzene in diethyl ether; the reaction mixture is refluxed and then treated with the major portion of the 4-chloro-bromobenzene in diethyl ether (the total amount of diethyl ether is about 200 ml.). After refluxing the reaction mixture until all of the magnesium has reacted, it is cooled, and 48.0 g. of 1,2-dichloro-diethyl ether is added over a period of one hour while cooling. The reaction mixture is then stirred at room temperature for thirty minutes and refluxed for one hour, and is allowed to stand overnight. It is poured onto a mixture of hydrochloric acid and ice; the organic material is extracted with diethyl ether, the organic solution is Washed quickly with 20 per cent aqueous sodium hydroxide and twice with water, dried, and concentrated. The desired 2-(4-chloro-phenyl)-2- ethoxy-ethyl chloride is isolated by distilling the residue and collected at 122140/ 12 mm.

Example 24 A mitxure of 16.0 g. of 2-(4-chloro-phenyl)-2-ethoxyethyl chloride and 11.8 g. of l-phenyl-piperazine in 200 ml. of n-butanol is refluxed for 24 hours in the presence of 40.0 g. of sodium carbonate. The inorganic material is filtered off, the filtrate is concentrated and the residue is distilled to yield the 1-[2-(4-chloro-phenyl-2- ethoxy-ethyl]-4-phenyl-piperazine of the formula.

OCzHn /CHz E2 CR -CH which is collected at 90-91/0.3 mm. and converted into its dihydrochloride, M.P. 203-205 (after recrystallization from acetonitrile).

Example 25 A mixture of 11.8 g. of 2-ethoxy-2-phenyl-ethyl chloride and 12.3 g. of 1-(Z-methoxy-phenyl)-piperazine in 200 ml. of n-butanol is refluxed for 24 hours in the pres ence of 40.0 g. of sodium carbonate. The inorganic material is filtered oft", the filtrate is concentrated and the residue is distilled to yield the 1-(2-ethoxy-2-phenylethyl)-4-(2-methoxy-phenyl)-piperazine of the formula OCH;

which is collected at 179-180/0.9 mm. and converted into its dihydrochloride, M.P. 215-217" (after recrystallization from ethanol and acetonitrile).

Other compounds, which are prepared according to the above procedure, are for example:

1 (2 ethoxy 2 phenyl ethyl) 4 phenyl piperazine, B.P. 177-180/0.35 mm., the dihydrochloride of which melts at 225-228";

1 [2 ethoxy 2 (3 trifluoromethyl phenyl) 20 ethyl]-4-phenyl-piperazine, B.P. 128-l40/0.35 mm., the dihydrochloride of which melts at l82-185;

4 (2 chloro phenyl) 1 (2 ethoxy 2 phenyl ethyl)-piperazine, B.P. 200-205/ 0.55 mm., the hydrochloride of which melts at 200-203 (after recrystallization from ethyl acetate);

- (2 ethoxy 2 phenyl ethyl) 3 methyl 4 phenyl-piperazine, collected at -180/ 0.5 mm., the

dihydrochloride of which melts at 230-235 (after recrystallization from ethanol);

1 [2 (3,4 dichloro phenyl) 2 ethoxy ethyl] 4--(2-rnethoxy-phenyl)-piperazine, collected at 210- 220/ 0.7 mm., the dihydrochloride of which melts at 221225 (after recrystallization from ethanol and diethyl ether);

4 (2 chloro phenyl) 1 [2 (4 chloro phenyl) Z-ethoxy-ethyl]-piperazine, collected at 185-190/0.2 mm., the hydrochloride of which melts at 240-244 (after recrystallization from ethanol);

1 [2 (3,4 dichloro phenyl) 2 ethoxy ethyl] 4-phenyl-piperazine, collected at 210-220/0.7 mm., the dihydrochloride of which melts at 211-213 (after recrystallization from ethanol and diethyl ether);

1 [2 (3 chloro phenyl) 2 ethoxy ethyl] 4 (Z-rnethoxy phenyl) piperazine, collected at 190/0.7 mm., the dihydrochloride of which melts at 213-217" (after recrystallization from ethanol and diethyl ether);

1 [2 (3 chloro phenyl) 2 ethoxy ethyl] 4 phenyl-piperazine, collected at -200/0.7 mm., the dihydrochloride of which melts at 192-193" (after recrystallization from ethanol and diethyl ether);

4 (3 methyl phenyl) 1 (2 ethoxy 2 phenyl ethyl)-piperazine, collected at -190/ 0.2 mm., the dihydrochloride of which melts at 197-199 (after recrystallization from ethanol);

1 [2 ethoxy 2 (4 fiuoro phenyl) ethyl] 4 (3 methyl phenyl) piperazine, collected at 160- 185/0.8 mm., the hydrochloride of which melts at 193-l96 (after recrystallization from ethanol and diethyl ether);

1 (2 ethoxy 2 phenyl ethyl) 4 (2 pyridyl) piperazine, collected at 185-190/0.5 mm., the dihydrochloride of which melts at 125-130 (after recrystallization from ethanol and diethyl ether);

as well as 4 (2 chloro phenyl) 1 [2 (4 chloro phenyl) 2 ethoxy ethyl] piperazine, 1 [2 ethoxy 2 (4 methyl phenyl) ethyl] 4 (2 methyl phenyl) piperazine, 1 (2 ethoxy 2 phenyl ethyl) 4 (4 pyridyl) piperazine, 1 (2 methoxy 2 phenyl ethyl) 4 phenyl 1,4 diaza cycloheptane, l (2 isopropyloxy 2 phenyl ethyl) 5 (3 methyl phenyl) 1,5 diaza cyclo octane, 1 (4 ethoxy 4 phenyl butyl) 4 phenyl piperazine, l [4 (4 chloro phenyl) 4 ethoxy butyl] 4 (2 methoxy-phenyl)-piperazine and the like.

Example 26 A mitxure of 10.6 g. of l-(3-methyl-phenyl)-pip erazine, 11.9 g. of 3-ethoxy-3-phenyl-propyl chloride and 6.4 g. of sodium carbonate in 250 ml. of ethanol is refluxed for 18 hours while stirring, then cooled and filtered. The filtrate is evaporated under reduced pressure and the residue is distilled to yield the l-(3-ethoxy-3-phenyh propyl)-4-(3-m.ethyl-phenyl)-piperazine of the formula 00 m Clan-CH,

CH -CH H which is collected at 172174/ 0.05 mm. The dihydrochloride, which is prepared by treating an ethanol solution of the free base with a saturated solution of hydrogen chloride in ethanol, melts at 166 after recrystallization from ethanol; yield: 3.6 g.

I phenyl) -piperazine of the formula on which is collected at 206210/ 0.13 mm. and converted into its dihydrochloride, which melts at 200 after recrystallization from isopropanol.

Example 28 A solution of 2,530 g. of 1-[3-hydroxy-3-(4-methyl phenyl) -propyl] -4- (Z-methyl-phenyl) -piperazine in 19,000 ml. of benzene is gassed with hydrogen chloride until thepH is 2. The hydrochloride salt precipitates, and the reaction mixture is treated with a solution of 2,750 g. of thionyl chloride in 12,000 ml. of benzene, while maintaining the temperature below 30. ing and stirring for twohours, the benzene and the excess of thionyl chloride are evaporated; the residue is diluted with 8,000 ml. of benzene and again evaporated to remove the remaining thionyl chloride. The residue is taken up into 12,000 ml. of anhydrous ethanol.

A solution of 718 g. of sodium in 23,400 ml. of an hydrous ethanol is cooled to and added to the above solution while cooling and keeping the temperature below After completion of the addition, the reaction mixture is refluxed for one hour, and is then allowed to stand overnight. The solution is evaporated to dryness, the residue is dissolved in 80,000 ml. of water while cooling, and the oily product is extracted with one portion of 40,000 rnl. and two portions of 20,000 ml. each of chloroform. The combined organic extracts are dried over sodium sulfate, treated with 150 g. of a charcoal preparation, and evaporated to dryness to yield 2,700 g. of 1-[3-ethoxy-3-(4-methyl-phenyl)'-propyl]-4-(2-methylphenyl)-piperazine, which is dissolved in 12,200 ml. of methanol. The organic solution is gassed with hydrogen chloride until the pH is 2 while maintaining the temperature below 40. After stirring at room temperature for three hours, the precipitate is filtered off, washed three times with three portions of 1,000 ml. each of cold methanol and dried at 60 under reduced pressure. The resulting 1- 3-ethoxy-3 (4-methyl-phenyl -propyl] -4- (Z-methyl-phenyl)-piperazine dihydrochloride melts at 165-168.

The starting material used in the above procedure is prepared as follows: A mixture of 2,490 g. of 1-(2- methyl-phenyl)-piperazine .dihydrochloride, 285.0 g. of paraformaldehyde and 1,735 g. of 4-methylfacetophenone in 7,500 ml. of anhydrous ethanol is refluxed for twentytWo hours while stirring. After cooling to -10, the precipitate is filtered off and washed three times with 1000 ml. of cold acetone. The resulting 1-[3-(4-methylphenyl)-3-oxo-propyl]-4-(2-methyl-phenyl) piperazine hydrochloride is dried overnight at 50 under reduced pressure, and melts at 209211; yield: 2,850 g.

The pH ofa solution of 2,660 g. of 1-[3-(4-methylphenyl)-3-oxo-propyl]-4-(2-methyl-phenyl) piperazine hydrochloride in 10,800 ml. of methanol is adjusted to 10 by adding a 50 percent aqueous solution of sodium hydroxide. After cooling to 6, a total of 407 g. of sodium borohydride is added over a period of one hour, maintaining theternperature between 6 and After warming to and stirring for three hours, the reaction mixture is acidified to pH 2 with concentrated hydro.-

The residue is distilled to yield the 1-- After refiuxchloric acid, and is again stirred for twenty minutes. The reaction mixture is diluted with 18,000 ml. of water and 11,000 ml. of chloroform, and while stirring and cooling to 25, the pH is again adjusted to 10 with a 50 percent solution of sodium hydroxide in Water. The organic layer is separated, the aqueous phase is extracted with two additional portions of 7,000 ml. each of chloroform. The combined organic extracts are dried over sodium sulfate, filtered and evaporated. The oily residue crystallizes to yield the 1-[3-hydroxy-3-(4-methylphenyl)-propyl]-4-(2-methyl phenyl)-piperazine, which melts at 83; yield: 2,530 g. 1

Example 29 A mixture of 8.9 g. of 3-ethoxy-3-phenyl-propyl-arnine and 11.6 g. of N,N-di-(Z-chloroethyl)-N-(3-methy1- phenyl)-amine in 50 ml. of methanolcontaining an excess of potassium carbonate is refluxed for fifteen hours while stirring. The solid material is filtered 01f, the filtrate is concentrated under reduced pressure and the residue is distilled to yield the 1-(3-ethoxy'3-phenylpropyl)-4-(3-methyl-phenyl)-piperazine, which is collected at l72174/0.05 mm., and isconverted into its dihydrochloride, MP. 166.

The starting material used in the above procedure is prepared as follows: A mixture of 21.3 g. of 3-ethoxy-3- phenylpropyl chloride and 22.0 g. of potassium phthalimide in 40 ml. of N,N-dimethylformamide is refluxed for two hours in the presence of a few crystals of potassium iodide as a catalyst. The hot solution is poured onto 150 g. of crushed ice; the organic material is extracted with chloroform, and the extract is washed with a 1 N aqueous solution of potassium hydroxide, 0.5 N aqueous hydrochloric acid and water. 1 After drying over sodium sulfate, the organic solution is concentrated to dryness under-reduced pressure. The residueis treated with ml. of methanol containing 10 ml. of hydrazine hydrate (99 100%) and refluxed for two hours. The solution is cooled, acidified with concentrated hydrochloric acid and again refluxed thirty minutes. After filtration, it is taken to dryness under reduced pressure; the residue is dissolved in a minimum amount of water and the aqueous solution ismade strongly alkaline with a 50 percent solution of potassium hydroxide, salted with potassium carbonate and extracted with diethyl ether. The organic extract is dried and concentrated under reduced pressure to yield the 3- ethoxy-3-phenyl-propylamine, which is used in the sub sequent step without further purification. U The N,N di (2 chloroethyl) -N-(3-methyl-phenyl)- amine used in the above procedure is prepared by heating a mixture of B-methyl-aniline and ethylene oxide in a sealed tube and converting the hydroxyl groups in a resulting N,N di-( Z-hydroxyethyl)-N-(3-methyl-pl1enyl)- amine into chloro by treatment with thionyl chloride.

Example 30 A mixture of 15.2 g of N,N-di-(2-chloroethyl)-N (3- ethoxy-3-phenyl-propyl)-amine and 5.4 g. of rn-toluidine in 100 ml. of methanol is refluxed in the presence of an excess of sodium carbonate for fifteen hours while stirring. The solid material is filtered off, the filtrate is evaporated to dryness, and the residue is distilled to yield' the I-( 3 -ethoxy-3 -phenyl-propyl -4-( 3 -methyl-phenyl) -pi- "perazine, which is collected at 172-174/0.5 mm. and

23 13.4 g. of N-(3-ethoxy-3-phenyl-propyl)-N,N-di-(2-hydroxyethyl)-amine while cooling. After refluxing for one hour, the resulting solution is poured onto ice, the chloroform layer is separated, dried and concentrated under reduced pressure to yield the N,N-di-(2-chloroethyl)-N- (3-ethoxy-3-phenyl-propyl)-amine.

Example 31 A solution of 14.12 g. of 4-(2-chloro-phenyl)-1-[3-(4- chloro-phenyl)-3-hydroxy-propyl]-piperazine in 100 ml. of benzene is gassed with hydrogen chloride until the pH is 2. The hydrochloride salt precipitates, and the reaction mixture is treated with a solution of 13.8 g. of thionyl chloride in 60 ml. of benzene, While maintaining the temperature below 30. After refluxing and stirring for two hours, the solvent and the excess of thionyl chloride are evaporated; the residue is diluted with 40 ml. of benzene and again evaporated to remove the remaining thionyl chloride. The residue is taken up into 60 ml. of anhydrous ethanol, and a cold solution of 3.59 g. of sodium in 120 ml. of anhydrous ethanol is added while keeping the temperature below 15 After completion of the addition, the reaction mixture is refluxed for one hour, and is then allowed to stand overnight. The solution is evaporated to dryness, the residue is dissolved in 400 ml. of water while cooling, and the organic material is extracted with three portions of chloroform. The combined organic extracts are dried over sodium sulfate, treated with a charcoal preparation, and evaporated to dryness to yield the 4-(2-chloro-pl1enyl)-1-[3-(4-chloro-phenyl)-3-ethoxypropyH-piperazine. A methanol solution of the latter is treated with hydrogen chloride until the pH is 2, while cooling to below 40. After stirring for three hours, the precipitate is filtered E, washed three times with cold methanol and dried at 60 under reduced pressure. The resulting 4 (2-chloro-phenyl)-1-[3-(4-chloro-phenyl)-3- ethoxy-propyl]-piperazine dihydrochloride melts at 120 after recrystallization from acetone.

The starting material used in the above procedure is prepared as follows: A mixture of 27.8 g. of 1-(2-chlorophenyl)-piperazine dihydrochloride, 3.85 g. of paraformaldehyde and 20.0 g. of 4-chloro-acetophenone in 75 ml. of anhydrous ethanol is refluxed for twenty-two hours while stirring. After cooling to l=O', the precipitate is filtered oil and washed three times with cold acetone. The resulting 4-(2-chloro-phenyl)-1-[3-(4-chloro-phenyl)-3-oxo-propyl] -piperazine hydrochloride is dried overnight at 50 under reduced pressure, and is used without further purification.

A solution of 30 g. of 4-(2-chloro-phenyl)-1-[3-(4- chloro-phenyl)-3-oxo-propyl] -piperazine hydrochloride in 120 ml. of methanol is made basic with a 50 percent aqueous solution of sodium hydroxide, is cooled to 6, and treated with a total of 4.07 g. of sodium borohydride which is added over a period of one hour, while maintaining the temperature below 20. After stirring for three hours at room temperature, the reaction mixture is acidified with concentrated hydrochloric acid, and is again stirred for twenty minutes. The reaction mixture is diluted with 200 ml. of water and 120 ml. of chloroform, and while stirring and cooling to 25, the reaction mixture is again made basic by adding a 50 percent solution of sodium hydroxide in water. The organic layer is separated, the aqueous phase is extracted with two additional portions of chloroform. The combined chloroform extracts are dried over sodium sulfate, filtered and evaporated. The residue, representing the 4-(2-chlorophenyl) -1-[3- (4-chloro-phenyl)-3-hydroxy propyl] -piperazine, is used withoout further purification.

Example 32 A mixture of 10 g. of Z-ethoxy-Z-(4-fluoro-phenyl)- ethyl chloride and 8.7 g. of 2-methyl-l-phenyl-piperazine in 200 ml. of butanol containing a few drops of water together with 10.0 g. of sodium carbonate is refluxed for 72 hours while stirring. The reaction mixture is filtered, the filtrate is concentrated under reduced pressure, and the residue is taken up into diethyl ether. The insoluble material is filtered off, and the filtrate is washed with water, dried and concentrated under reduced pressure. The desired 1- [2-ethoxy-2-(4-fluoro-phenyl)-ethyl]-3- methyl-4-phenyl-piperazine of the formula is distilled, collected at 170175/ 0.6 mm., and converted into its dihydrochloride by treatment with an ethanol solution in hydrogen chloride; the salt melts at 228-232 after recrystallization of ethanol and diethyl ether.

The starting material used in the above example is prepared as follows: A mixture of 8.16 g. of magnesium turnings in 275 ml. of diethyl ether is treated with 70 g. of 4-bromo-fluoro-benzene to form the Grignard reagent, which is stirred for another hour while cooling and is then treated dropwise with 48 g. of 1,2-dichloroethy1 ether ether. After completion of the addition, the reaction mixture is stirred for thirty minutes at room temperature, then refluxed for one hour and allowed to stand at room temperature overnight. It is then poured onto ice; the aqueous mixture is acidified with concentrated hydrochloric acid and is extracted with diethyl ether. The organic solution is dried and evaporated and the residue is distilled to yield the 2-ethoxy-2-(4-fluoro-phenyl)-ethyl chloride, which is collected at -115/ 12 mm.

Example 33 A mixture of 11.9 g. of l-(3-methoxy-phenyl)- piperazine, 7.5 g. of sodium carbonate and 11.2 g. of 3-ethoxy-3-phenyl-propyl chloride in 100 ml. of ethanol is refluxed for forty-eight hours. After cooling, the inorganic material is filtered off, the filtrate is evaporated under reduced pressure and the viscous residue is treated with a small amount of diethyl ether, the solid material is filtered off, washed with water and extracted with diethyl ether. After drying over magnesium sulfate, the solvent is evaporated and the resulting 1-(3-ethoxy-3- phenyl-propyl) -4-(3-methoxy-phenyl) -piperazine of the formula is purified by distillation and converted into its dihydrochloride which melts at 163 after recrystallization from ethanol.

Example 34 A solution of 24.4 g. of 1-(2-hydroxy-2-pheny1-ethyl)- 4-(2-methoxy-phenyl)-piperazine in benzene is treated with hydrogen chloride gas until the pH is about 2. The hydrochloride salt precipitates, and the reaction mixture is treated with a solution of 27.5 g. of thionyl chloride in m1. of benzene, while maintaining the temperature below 30. After refluxing and stirring for two hours, the benzene and the excess of thionyl chloride are evaporated; the residue is diluted with 100 m1. of benzene and again evaporated to remove the remaining thionyl chloride. The residue is taken up into 120 ml. of anhydrous ethanol, and treated with a solution of 7.2 g. of sodium in 250 ml. of anhydrous ethanol while cooling and keeping the temperature below 15. After completion of the addition, the reaction mixture is refluxed for one hour, and is then allowed to stand overnight. The solution is evaporated to dryness, the residue is dissolved in 800 ml. of water while cooling, and the oily product is extracted with chloroform. The organic extract is dried over sodium sulfate, treated with a charcoal preparation, and

. 255 t r evaporated to dryness to yield the 1-(2-ethoxy-2-phenylethyl) -4-(2-methoxy-phenyl) -piperaz.ine, which is purified by distillation and collected at 179l80/0.9 mm. The 1 (2 ethoxy-2-phenyl-ethyl) 4 (2-methoxy-phenyl)- piperazine dihydrochloride is obtained by reacting the 1-(2 ethoxy 2 phenyl-ethyl) 4 (2-methoxy-phenyl)- piperazine with hydrogen chloride as described above and melts at 215-217 after recrystallization from ethanol and acetonitrile. I l i The starting material used in the above procedure is prepared by reacting 1-(2-methoxy pheny1)-piperazine wit-h a-chloroacetophenone in the presence of sodium carbonate, and reducing the carbonyl portion in the resulting 4-(2-methoxy-phenyl) 1'- (2-oxo-2-phenyl-ethyl) -piperazine by treating a methanol solution of the latter with sodium borohydride at a pH of about 10, brought about by adding sodium hydroxide.

Example 35 A mixture of 8.9 g. of 2-ethoxy-2-phenyl-ethyl-amine and 12.4 g. of N,N-di-(Z-chloroethyl)-N-(2-methoxyphenyl)-amine in 50 ml. of methanol is refluxed for fifteen hours while stirring in the presence of an excess of potassium carbonate. The solid material is filtered otf, the filtrate is concentrated under reduced pressure and the residue is distilled to yield the l-(2-ethoxy-2-phenylethyl)-4-(2-methoxy-phenyl)-piperazine, which is collected at 179180/ 0.9 mm., and is converted into its'dihydrochloride, M.P. 215-217", after recrystallization from ethanol and acetonitrile.

The starting material used in the above procedure is prepared by refluxing a mixture of Z-ethoxy-Z-phenylethyl chloride and potassium phthalimide in N,N-dimethylformamide, and converting the resulting N-(-2- ethoxy-Z-phenyl-ethyl)-phthalimide into the desired 2- ethoxy-Z-phenyl-ethyl-amine by refluxing a methanol solution of the former with hydrazine hydrate.

The N,N-di-(2-chloroethyl) N (Z-methoxy-phenyD- amine used in the above procedure is prepared by heating a mixture of Z-methoxy-aniline and ethylene oxide in a sealed tube and converting the hydroxyl groups in a resulting N,N di (Z-hydroxyethyl)-N-(2-methoxy-phenyl)- amine into chloro by treatment with thionyl chloride.

Example 36 A mixture of 7.6 g. of N,N-di-(Z-chloroethyl)-N-(2- ethoxy-Z-phenyl-ethyl)-amine and 6.2 g. of 2-methoxyaniline in 50 ml. of methanol is refluxed in the presence of an excess of sodium carbonate for fifteen hours while stirring. The solid material is filtered off, the filtrate is evaporated to dryness, and the residue is distilled to yield the 1 (2-ethoxy-2-phenyl-ethyl)- 4-(2-rnethoxy-phenyl)- piperazine, which is collected at 179180/0.9 mm. and converted into its dihydrochloride, M.P. 215217 after recrystallization from ethano and acetonitrile.

The starting material used in the above procedure is prepared by heating a'mixture of 2-ethoxy-2-phenyl-ethylamine and ethylene oxide in a sealed tube at 130 for sixteen hours, and reacting the resulting N-(2-ethoxy-2- phenyl-ethyl) -N,N-di-(2-hydroxyethyl)-amine with a suspension of powdered phosphorus pentachloride in dry chloroform at an elevated temperature.

What is claimed is:

'1. A member selected from the group consisting of an N-(x-lower alkoxy-x-monocyclic carbocyclic aryl-lower alkyl)-N'-monocyclic aryl-diaza-cycloalkane, in which lower alkoxy and monocyclic carbocyclic aryl substitute the same carbon atom and areseparated from the nitrogen atom of the diaza-cycloalkane portion by two to four carbonatoms, and in which the diaza-cycloalkane portion has from six to eight ring members, and its two nitrogen atoms are separated from one another by from two to three carbon atoms of alkylene radicals having from two to seven carbon atoms, and in which monocyclic carbocyclic aryl is a member selected from the group consisting in which R is lower alkyl, the at... is the integer 26 r of phenyl, (lower alkyl)-phenyl, (lower alkoxy)-phenyl, (halogeno).-phenyl and (trifluorornethyD-phenyl, and monocyclic aryl is a member selectedfrorn the group consisting of phenyl, (lower alkyl) pheny1', (lower alkoxy)- phenyl, (halogeno)-phenyl and pyridyl, acid addition salts thereof, N-oxides thereof, acid addition salts of N-oxides thereof, and. lower alkyl quaternary ammonium compounds thereof.

2. A compound of the formula O-R g Q-H-(CHzh-N N' fa. i i i Rs 2, the radical R stands for hydrogen, and each of the groups R and R stands for lower alkyl.

3. A compound of the formula R, r Rb in which R is lower alkyl, the letter m is the integer 2, the radical R stands for hydrogem'the group R is halogeno, and the group R stands for hydrogen.

4. A compound of the formula in which R is lower alkyl.

5. An acid addition salt of a compound of the formula CH -OE; l

Rb in which R is lower alkyl, the letter m is the integer 1, R is hydrogen, R,,' is hydrogen, and R is methoxy.

9. A compound of the formula in which R is lower alkyl, the letter m is the integer 1, R is hydrogen, R, is halogeno, and R is methoxy.

10. 1-[3-(4-chloro-phenyl)-3-ethoxy propyl] -4-phenylpiperazine.

11. An acid addition of 1-[3-(4-chloro-phenyl)- 3- ethoxy-p ropyl] -4-phenyl-piperazine.

12. '1- [3- (4-ch1oro-phenyl) -3-ethoxy-propyl] -3-methyl- 4-phenyl-piperazine.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,168, 522 February 2, 1965 George de Stevens et al.

It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 26, lines 34 to- 38, for the right-hand portion of the formula reading read ClH 3 column 26, lines 55 to 59, for that portion of the formula reading /CH ---CH /CH -'---CH /N- read CH -CH CH R1 same column 26, line 70, for "-ethoxy propyl" read --ethoxy propyl line 72, for "addition" read addition salt column 27, line 12, for "2-" read (2- line 20, for

"-methylphenyl" read -methylphenyl column 28, line 11, for "2(4" read 2- (4- Signed and sealed this 26th day of October 1965.

(SEAL) Attest:

ERNEST W. SWIDER EDWARD J, BRENNER Attesting Officer Commissioner of Patents 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF AN N-(X-LOWER ALKOXY-X-MONOCYCLIC CARBOCYCLIC ARYL-LOWER ALKYL)-N''-MONOCYLIC ARYL-DIAZA-CYCLOAKLANE, IN WHICH LOWER ALKOXY AND MONOCYCLIC CARBOCYCLIC ARYL SUBSTITUTE THE SAME CARBON ATOM AND ARE SEPARATED FROM THE NITROGEN ATOM OF THE DIAZA-CYCLOALKANE PORTION BY TWO TO FOUR CARBON ATOMS, AND IN WHICH THE DIAZA-CYCLOALKANE PORTION HAS FROM SIX TO EIGHT RING MEMBERS, AND ITS TWO NITROGEN ATOMS ARE SEPARATED FROM ONE ANOTHER BY FROM TWO TO THREE CARBON ATOMS OF ALKYLENE RADICALS HAVING FROM TWO TO SEVEN CARBON ATOMS, AND IN WHICH MONOCYCLIC CARBOCYCLIC ARYL IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF PHENYL, (LOWER ALKYL)-PHENYL, (LOWER ALKOXY)-PHENYL, (HALOGENO)-PHENYL AND (TRIFLUOROMETHYL)-PHENYL, AND MONOCYCLIC ARYL IS A MEMBER SELECTED FROM THE GROUP CONSISTING OF PHENYL, (LOWER ALKYL)-PHENYL, (LOWER ALKOXY)PHENYL, (HALOGENO)-PHENYL AND PYRIDYL, ACID ADDITION SALTS THEREOF, N-OXIDES THEREOF, ACID ADDITION SALTS OF N-OXIDES THEREOF, AND LOWER ALKYL QUATERNARY AMMONIUM COMPOUNDS THEREOF. 